There is interest in the use of bioorthogonal reactions for live-cell applications. Additional bioorthogonal reactions may expand the toolbox of researchers for live-cell applications. The lack of convenient synthetic methods has been a significant roadblock to broader use and study by the scientific community. Accordingly, there is a need for a convenient synthetic route to synthesize tetrazine derivatives that can aid in live-cell applications. Provided herein are solutions to these and other problems in the art.